There is great interest in developing injectable, biocompatible compositions that can provide long-term release of a protein. It would be particularly advantageous to develop biocompatible and biodegradable compositions that release therapeutic levels of biologically active protein at a controlled rate for one, two, or three months or more.
Biodegradable compositions, such as intraocular implants, capable of delivering therapeutic levels of functional protein for extended periods could be extremely useful for the treatment of ocular disease, where the use of proteins, such as antibodies, typically requires frequent intraocular injection or high systemic dosing.
Aside from the discomfort and time associated with frequent injections, direct intraocular injection can involve certain risks to the patient, including retinal detachment, damage to the lens, and infection. Direct intraocular injection may also result in localized toxicity due to high pulsed concentrations of the protein drug at the lens and other intraocular tissues. Additionally, penetration of systemically administered proteins into the retina is severely restricted by the blood-retinal barriers (BRB).
Compounds are typically eliminated from the vitreous of the eye by diffusion to the retro-zonular space with clearance via the aqueous humor, or by trans-retinal elimination. Most high molecular weight compounds utilize the former pathway while lipophilic compounds and those with trans-retinal transport mechanisms will utilize the latter. Unfortunately, compounds that are eliminated across the retina have extremely short half-lives. Hence, for these compounds it is difficult to maintain therapeutic concentrations by direct intraocular injection. Frequent injection would be required. Even for macromolecules, such as proteins, that are cleared out via the aqueous humor, the vitreal half-life is short relative to the duration of therapy. Therefore, compounds such as LUCENTIS® must be dosed as frequently as once per month by intravitreal injection.
It would therefore be of great value to patients to obviate the need for frequent injections of proteins by developing biodegradable implants that can provide for the safe, effective, and long-term release of biologically active protein in a single dose while avoiding the high transient concentrations associated with pulsed dosing.